The infective process of HIV-1 in vivo has been the subject of a review article by McCune, Cell, 64: 351-363 (1991). Briefly, HIV-1 infects a variety of cell lineages, such as T-cells, monocytes/macrophages and neuronal cells, which express the CD4 receptor. Because the vast majority of CD4.sup.+ cells in the body are "resting" or quiescent and divide only in response to specific signals, infection with HIV-1 results in CD4.sup.+ cells harboring transcriptionally inactive virus. Stimulation of the immune system of infected animals, including active immunization, may result in polyclonal activation and the signaling of resting CD4.sup.+ cells to go into the S phase of the cell cycle. The replicating cells then actively produce viral particles, provoking spread of the infection. Considering this negative effect of stimulating the immune system of an HIV-1-infected animal, it is possible that the most effective method of preventing or treating HIV-1 infection is passive immunization, that is, administering anti-HIV-1 antibodies to a susceptible or infected animal.
Jackson et al., Lancet, 2: 647-652 (1988) reports that a single administration of anti-HIV-I antibodies in the form of plasma to human patients afflicted with advanced acquired immunodeficiency syndrome (AIDS, the syndrome of progressive immune system deterioration associated with HIV-I infection) temporarily resulted in: fewer symptoms, a transient increase in T lymphocytes, a reduction in the frequency of opportunistic infections and a decline in the rate at which HIV-1 could be cultured from plasma or lymphocytes of the patients. See also, Karpas et al., Proc. Natl. Acad. Sci. USA, 85: 9234-9237 (1988). Moreover, Emini et al., Nature, 355: 728-730 (1992) reports that the administration of an antibody specifically reactive with HIV-1 to a chimpanzee before the animal was exposed to HIV-1 resulted in the chimpanzee remaining free of signs of viral infection. These studies indicate that antibodies capable of neutralizing HIV-1 can be useful in the prevention/treatment of HIV- 1 infection.
The HIV-1 major external envelope glycoprotein, gp120, binds to the cellular CD4 receptor and facilitates the internalization of the virus. Several epitopes of the glycoprotein have been associated with the development of neutralizing antibodies. Ho et al., Science, 239: 1021-1023 (1988) reports that amino acids 254-274 of gp120 elicit polyclonal antisera capable of group-specific neutralization of three different isolates of HIV-1. Conformation-dependent epitopes, epitopes not consisting of primary sequences of amino acids, on gp120 have also been implicated in eliciting antibodies that neutralize diverse strains of the virus by Haigwood et al., Vaccines 90: 313-320 (1990) and Ho et al., J. Virol., 65(1): 489-493 (1991). The so-called "principal neutralizing determinant" (PND) of HIV-1 gp120 has been localized to the "V.sub.3 loop" of gp120. See Putney et al., Science, 234: 1392-1395 (1986); Rusche et al., Proc. Natl. Acad. Sci. USA, 85: 3198-3202 (1988); Goudsmit et al., Proc. Natl. Acad. Sci. USA, 85: 4478-4482 (1988); Palker et al., Proc. Natl. Acad. Sci. USA, 85: 1932-1936 (1988); and Holley et al., Proc. Natl. Acad. Sci. USA, 85: 6800-6804 (1991). The V.sub.3 loop consists of a hypervariable domain which is established by disulfide bonding between cysteine residues flanking the domain. The V.sub.3 loop of HIV-1.sub.MN, for example, is formed by a disulfide bond between the cysteine residues at positions 302 and 336 of gp120.
Recombinant and synthetic protein fragments including the series of amino acid residues of the V.sub.3 loop from various HIV isolates have been reported to elicit isolate- or type-specific neutralizing antibodies in rodents by Lasky et al., Science, 233: 209-212 (1986); Palker et al., supra; Matsushita et al., J. Virol., 62: 2107-2114 (1988); and Javaherian et al., Proc. Natl. Acad. Sci. USA, 86: 6768-6772 (1989). More recent studies [Putney et al., supra and LaRosa et al., Science, 249: 932-935 (1990)] have demonstrated that the .beta.-turn structure of the V.sub.3 loop is the site recognized by the isolate-specific antibodies. Scott et al., Proc. Natl. Acad. Sci. USA, 87: 8597-8601 (1990) report that the PND can also induce a type-specific antibody in humans. The hypervariability of the PND may account for the type-specific neutralizing activity generated by the epitope.
Several studies have suggested that antibodies prepared against recombinant gp120, purified gp120 or synthetic peptides from V.sub.3 domain can neutralize diverse HIV-1 isolates. Javaherian et al., Science, 250: 1590-1593 (1990) and Weiss et al., Nature, 324: 572-575 (1986) each describe neutralization of both MN and III.sub.B isolates by polyclonal sera from rabbits respectively immunized with a peptide corresponding to the PND of MN isolates and with a recombinant gp120 derived from a III.sub.B isolate. See also, Haynes et al., U.S. Pat. No. 5,019,387.
Akerblom et al., AIDS, 4: 953-960 (1990) describes monoclonal antibody preparations that neutralize III.sub.B and eleven primary HIV-1 isolates. See also, Patent Cooperation Treaty (PCT) Publication No. WO 91/11198 of Wahren et al., published on Aug. 8, 1991. The strain homology of the Akerblom primary isolates is not determined, however, and the eleven isolates may also be III.sub.B. Durda et al, AIDS Res. Hum. Retrov., 6: 1115-1123 (1990) report a monoclonal antibody that blocks syncytia formation by both MN- and III.sub.B -infected cells, but does not neutralize MN infectivity as determined by a "LAV capture immunoassay," an assay which is purported to give results that would correlate with reverse transcriptase activity. Patent Cooperation Treaty Patent Application No. WO 90/15078 of Scott et al., published on Dec. 13, 1990, describes monoclonal antibodies which inhibit syncytium formation by cells infected with vaccinia virus expressing the PND of MN or "MN-like" isolates. None of the assertedly "broadly neutralizing" antibodies are demonstrated, by means of standard reverse transcriptase, p24 or MT-2 assays, to neutralize multiple strains of live HIV-1. See also, PCT Publication Nos. WO 88/09181, WO 90/12868, WO 91/09625 of Tanox Biosystems, Inc., published on Dec. 1, 1988, Nov. 1, 1990 and Jul. 11, 1991, respectively; PCT Publication No. WO 91/19797 of New York University, published on Dec. 26, 1991; and Liou et al., J. Immunol., 143(12): 3967-3975 (1989). A broadly neutralizing antibody specific for the V.sub.3 region of HIV-1 gp120, monoclonal antibody NM01, is described in Ohno et al., Proc. Natl. Acad. Sci. USA, 88: 10726-10729 (1991) and in PCT International Publication No. WO 93/04090 published on Mar. 4, 1993.
The foregoing publications indicate that monoclonal antibodies reactive with the HIV-1 PND developed to date exhibit different levels of group reactivity, but may not have broad neutralizing activity. The different patterns of type- and group-specific reactivity indicated by these studies may be related to both the amino acid sequence and the conformation of the loop region of gp120.
There thus continues to exist a need in the art for new monoclonal antibody substances (including, e.g., murine-derived antibodies, humanized antibodies, and immunologically active antibody fragments) which are specifically immunoreactive with HIV-1. Ideally, such antibodies would be characterized by the ability to effect neutralization of multiple HIV-1 strains as determined by standard p24 assays involving suitable cultured host cells (e.g., H9 cells).